Hepatitis a viricide

ABSTRACT

The invention relates to agents which combat the hepatitus A virus, containing only minimal amounts of chlorine-containing and/or chlorine cleaving active ingredients, or none of said substances. The inventions also relates to the use of these agents and to a method for their production.

[0001] The present invention relates to compositions which act againsthepatitis A virucide and contain chlorine-containing and/or -releasingactive compounds only to a very small extent or not at all.

[0002] Hand disinfectants in general have only a very restrictedactivity against viruses. As a rule, only the ‘coated’ and/or lipophilicviruses are reached. These include hepatitis B virus, HIV and rotavirus.Many further viruses, but in particular the ‘uncoated’ hydrophilicviruses, on the other hand, are not reached by the customary handdisinfectants. Customary hand disinfectants are frequently designed onthe basis of alcohols having a total alcohol content of around 70% andare considered as inactive against the ‘uncoated’ hydrophilic viruses.Hepatitis A virus, probably the most important uncoated hydrophilicvirus in the human medicine and the foodstuffs field, is included here.Around 5000 to 6000 hepatitis A cases are reported per year for theFederal Republic alone. These represent, however, only about 5% of theactual cases of infection. 90 to 95% of the HAV infections proceedatypically or without a marked clinical picture and are therefore notcovered by the official statistics. The infection rate of HAV is thusmarkedly above such an important disease as, for example, HIV infection(less than 2000 new infections per year). In medical fields such aspediatrics, neonatology or infectious medicine, just as in the field offoodstuffs-processing plants, there is an urgent need for a handdisinfectant having specific activity against HAV. A fundamentalactivity against coated viruses (e.g. HIV, HBV) and also againstbacteria and fungi is moreover an obvious fundamental requirement ofsuch compositions, but has hitherto not been documented anywhere incombination with an HAV activity.

[0003] Hitherto, it is known that individual hand disinfectants havingan ethanol concentration of 80 to 90% by volume can have an activityagainst poliovirus. Although poliovirus is likewise an uncoatedparticle, the sensitivity of the poliovirus to disinfectant recipes ofthis type is regarded as an exception among experts.

[0004] It is therefore required as standard for the testing of thevirucidicity of hand disinfectants that they are tested against theuncoated simian virus 40. All hand disinfectants based on alcohol provedinactive here.

[0005] Despite this, there are manufacturers of hand disinfectants inthe market who, on account of the activity against poliovirus, offer avirucidal action against hepatitis A as a bonus. This conclusion is notcorrect, since, as explained above, an inference cannot be drawn from avirus which, as is known, is sensitive to disinfectants, on anothervirus, no matter which. It therefore held true to this day, despitethese products found on the market, for the profession that productsbased on alcohol have no activity against hepatitis A, since up to now ademonstration of such an activity has never been carried out.

[0006] Wallhäuβer occupies himself in his book “Praxis derSterilisation, Desinfektion, Konservierung” [Sterilization, Disinfectionand Preservation Practice], 5th edition, page 94-95, Georg Thieme VerlagStuttgart/New York, 1995, among other things, with disinfection whenworking with hepatitis viruses. Wallhäuβer refers there to the 11thedition of the listing of experimentally tested and recognized activedisinfectants and disinfection procedures required by the federal publichealth department of Germany according to §10c BSG and makes it clearthat only chloramine T in 1 percent and 2 percent concentration meetsthe requirements for activity against hepatitis A. Furthermore, twocommercial preparations, which are likewise based on chloro activecompounds, are mentioned as preparations which are considered as active.

[0007] Accordingly, the profession, although chloro active compounds arehazardous for ecological and toxicological reasons, has thus resigneditself to the fact that it is necessary to employ chlorine-containingcompositions for the control of hepatitis A. Compositions based onalcohol were considered without exception as inactive against hepatitisA viruses and were also classified as such in older editions of the BGAlist. Although the need for compositions which, without aid or only withvery greatly reduced amounts of chlorine-containing active compounds,have, as has been shown, an adequate activity against hepatitis A, wouldbe very large in the market, it was not to be expected that agents ofthis type can be made available. It was therefore an object of thepresent invention to seek compositions which, with contents ofchloro-active active compounds which are as low as possible, displayadequate action against hepatitis A viruses.

[0008] The present invention accordingly relates to a hepatitisA-destroying composition which contains one or more aqueous alcoholsand, if desired, 0.1 to 10% by weight of additional antimicrobialcomponents, with the proviso that less than 0.5% by weight ofchlorine-containing and/or chlorine-releasing active compounds arepresent, based on the total composition.

[0009] For the experts, it still applied that, explicitly for hepatitisA, no activity of such compositions exists. Therefore, despite theproducts mentioned offering HAV activity as a bonus, on account of theknowledge of the profession it was not obvious but surprising that HAVactivity was to be detected for compositions according to the invention.

[0010] In a preferred embodiment of the composition according to theinvention, the content of chlorine-containing and/or -releasing activecompounds is less than 0.3% by weight based on the total composition,the composition according to the invention particularly preferably beingfree of chlorine-containing and/or -releasing active compounds.

[0011] If a chlorine-containing and/or -releasing active compound isemployed in the composition according to the invention, then compounds,such as, for example, chlorhexidine gluconate,2,2′-methylenebis(6-bromo-4-chloro-phenol),2,4,4′-trichloro-2′-hydroxydiphenyl ether,N-(4-chlorophenyl)-N-(3,4-dichlorophenyl)urea,N,N′-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamideare preferred.

[0012] It is preferred that the composition according to the inventioncontains, as alcohol, 50 to 97% by weight, particularly preferably 80 to95% by weight, of ethanol based on the total composition, the remainderto of 100% total amount being water and/or other active compounds,optionally chlorine-containing and/or -releasing active compounds withinthe amounts specified.

[0013] Further additives which can be present in preferred embodimentsare, by way of example, customary fragrances, refatting agents andsurfactant components.

[0014] In a further preferred embodiment, the composition according tothe invention contains, as a further alcohol in addition to ethanol, 0.1to 40% by weight of one or more components selected from methanol,n-propanol, i-propanol, 1,3-butanediol, phenoxyethanol, 1,2-propyleneglycol and glycerol, where the contents of the alcohols and the othercomponents are to be chosen such that the sum of 100% is not exceeded.

[0015] Preferably, using the composition according to the inventionhepatitis A is inactivated at room temperature within less than 300seconds, particularly preferably within less than 120 seconds, and veryparticularly preferably within less than 60 seconds.

[0016] In a likewise preferred embodiment of the composition accordingto the invention, adequate effects against HAV can still be broughtabout even at very low temperatures of about 0° C.

[0017] As additional antimicrobial active compounds, the compositionaccording to the invention preferably contains, based on the totalcomposition, components which are particularly preferably selected fromthe groups consisting of the aldehydes, antimicrobial acids, Lewisacids, carboxylic acid esters, acid amides, phenols, phenol derivatives,diphenyls, diphenyl-alkanes, urea derivatives, oxygen and nitrogenacetals and also—formals, benzamidines, isothiazolines, phthalimidederivatives, pyridine derivatives, antimicrobial surface-activecompounds, guanidines, antimicrobial amphoteric compounds, quinolines,the additional chlorine-free antimicrobial component very particularlypreferably being selected from undecylenic acid, citric acid,p-hydroxybenzoic acid, sorbic acid, salicylic acid, quaternary ammoniumcompounds, guanidines and amphoteric compounds.

[0018] In particular, by addition of Lewis acids, for example zincchloride, aluminum chloride and barium chloride, to the compositionsaccording to the invention, it is possible to manage with reducedamounts of ethanol.

[0019] In a preferred embodiment, the composition according to theinvention is present as a liquid, gel, cream, paste or foam, ifappropriate it can also be present in the form of a combination with asolid carrier, which can be made available, for example, by impregnationor other treatment of paper, cloth fabrics or further suitable carriers.

[0020] The composition according to the invention preferably containsadditional surfaceactive components such as alkyl polyglycosides.

[0021] Preferred additional excipients in the composition according tothe invention are components which lead to the improvement of the skincompatibility, such as castor oil, glycerol or other alcohols, but whichwere already contained in the previous embodiments.

[0022] A further subject of the present invention is the use of acomposition according to the invention for the disinfective treatment ofskin surfaces, in particular in a microbiologically sensitive workingarea, very particularly in the hospital, kitchen, foodstuffs, cosmetics,pharmacy or household sector and very especially if requirements foraseptic working are made.

[0023] A further subject of the invention is a process for theproduction of a composition according to the invention according to theexplanations made in the present invention.

EXAMPLES

[0024] For the testing of the activity against hepatitis A, 2 differentrecipes were selected:

[0025] Recipe A:

[0026] 80% by weight of ethanol

[0027] 15% by weight of methanol

[0028] remainder to 100%:

[0029] additional chlorine-free excipients, such as refatting agents,perfume etc.. and water

[0030] Recipe B:

[0031] 90% by weight of ethanol

[0032] 0.2% by weight of chlorhexidine gluconate

[0033] remainder to 100%:

[0034] additional chlorine-free excipients, such as refatting agents,perfume etc.. and water

[0035] The suspension experiments for the testing of the activityagainst hepatitis A were carried out according to the guidelines of theBGA (Federal public health department) and the DVV (German veterinaryregulations).

[0036] The recipes A and B were incubated at room temperature with thehepatitis A virus according to the test procedure in 80% concentrationwithout and with albumin loading.

[0037] After the specified time of action, the virus-disinfectantsuspension was transferred to a microtiter plate prepared according tothe experimental procedures mentioned and subsequently diluted in log 10steps.

[0038] The dilutions were transferred to cell culture plates.

[0039] The toxicity controls were likewise carried out according to theguidelines of the BGA and of the DVV. Both in the case of recipe A andin the case of recipe B, cell damage no longer occurred at a dilution of10⁻³.

[0040] The result of the inactivation experiments can be summarized asfollows:

[0041] Both recipe A and recipe B inactivate the hepatitis A virus bothwithout and with albumin loading by more than 5 titer stages (log 10)with a time of action of at least 1 minute.

[0042] After a 5-minute time of action, residual infectiousness is nolonger detectable.

[0043] Thus it is confirmed for the first time that compositionsaccording to the invention have activity against hepatitis A.

1. A hepatitis A-destroying composition which contains one or moreaqueous alcohols and, if desired, 0.1 to 10% by weight of additionalantimicrobial components, with the proviso that less than 0.5% by weightof chlorine-containing and/or chlorine-releasing active compounds arepresent, based on the total composition.
 2. The composition as claimedin claim 1, characterized in that the alcohol present is 50 to 97% byweight of ethanol, based on the total composition, the remainder to 100%total amount being water and/or other active compounds.
 3. Thecomposition as claimed in claim 2, characterized in that, based on thetotal composition, as a further alcohol in addition to ethanol, 0.1 to40% by weight of one or more components selected from methanol,n-propanol, i-propanol, 1,3-butanediol, phenoxyethanol, 1,2-propyleneglycol and glycerol are present, where the contents of the alcohols areto be chosen such that the sum of 100% is not exceeded.
 4. Thecomposition as claimed in one of claims 1 to 3, characterized in thatthe additional antimicrobial components are selected from the groupsconsisting of the aldehydes, antimicrobial acids, Lewis acids,carboxylic acid esters, acid amides, phenols, phenol derivatives,diphenyls, diphenylalkanes, urea derivatives, oxygen and nitrogenacetals and also -formals, benzamidines, isothiazolines, phthalimidederivatives, pyridine derivatives, antimicrobial surface-activecompounds, guanidines, antimicrobial amphoteric compounds, quinolines,1,2-dibromo-2,4-dicyanobutane, iodo-2-propynylbutyl carbamate, iodine,iodophores.
 5. The composition as claimed in claim 4, characterized inthat the additional antimicrobial components are selected fromundecylenic acid, citric acid, p-hydroxybenzoic acid, sorbic acid,salicylic acid, 2-benzyl-4-chlorophenol,2,2′-methylenebis(6-bromo-4-chloro-phenol),2,4,4′-trichloro-2′-hydroxydiphenyl ether,N-(4-chloro-phenyl)-N-(3,4-dichlorophenyl)urea,N,N′-(1,10-decanediyldi-1-pyridinyl-4-ylidene)bis(1-octanamine)dihydrochloride,N,N′-bis-(4-chlorophenyl)-3,4-diimino-2,4,11,13-tetraazatetradecanediimid-amide,quaternary ammonium compounds, guanidines, amphoteric compounds.
 6. Thecomposition as claimed in claim 5, characterized in that the additionalantimicrobial components present are 2,4,4′-trichloro-2′-hydroxydiphenylether and/orN,N′-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide.7. The composition as claimed in one of claims 1 to 6, characterized inthat the composition is present as a liquid, gel, cream, paste or foamin combination with a solid carrier.
 8. The composition as claimed inone of claims 1 to 7, characterized in that additional surface-activecomponents are present.
 9. The use of a composition as claimed in one ofclaims 1 to 8 for the disinfective treatment of skin surfaces.
 10. Aprocess for the production of a composition as claimed in claims 1 to 8.